Wednesday, 24 July 2013

Interleukin 17 and Beta Interferon

Axtell RC, Raman C. Janus-like effects of type I interferon in autoimmune diseases. Immunol Rev. 2012;248:23-35

In multiple sclerosis, type I interferon (IFN) is considered immune-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. This is in contrast to most other autoimmune disorders, because type I IFN contributes to the pathologies. Even within the relapsing-remitting multiple sclerosis (RRMS) population, 30-50% of MS patients are non-responsive to this treatment, and it consistently worsens neuromyelitis optica, a disease similar to RRMS. In this article, we discuss the recent advances in the field of autoimmunity and introduce the theory explain how type I IFNs can be pro-inflammatory in disease that is predominantly driven by a Th17 response and are therapeutic when disease is predominantly Th1.


Potential mechanisms of how type IFN exacerbates autoimmune diseases
Autoimmune diseases initiated with the IL-23/Th17 response secrete high levels of IL-17A and IL-17F. IL-17A and IL-17F initiate granulocyte infiltration to the site of inflammation as well as orchestrate germinal center formation and B-cell maturation in lymphoid tissues. Endogenously expressed or therapeutically administered IFN-β could exacerbate Th17 diseases by directly stimulating granulocytes to release tissue destructive proteases and cytokines or by elevating BAFF to enhance the production of autoreactive antibodies and memory B-cells. Type I IFN also upregulates IL-22 receptor on skin epithelial cells in psoriatic skin and BBB endothelium in NMO. IL-22 can contribute to inflammation by promoting the release of defensins and breaking down tight junctions at the BBB.



Potential mechanisms on how type I IFN protects in RRMS
Autoimmune diseases initiated by Th1 cells have high levels of IFN-γ that drive lymphocytic and macrophage infiltration in to sites of inflammation. IFN-γ upregulates IL-7 expression in lymphoid tissue stromal cells during T-cell differentiation and provides signals to expand and maintain the Th1 population. IFN-β treatment synergizes with both IFN-γ and IL-7 to attenuate inflammation by upregulating the anti-inflammatory cytokines, IL-27 and IL-10, and decrease chemokine production from macrophages/microglial cells. Type I IFN also induces BAFF expression. BAFF then could directly or indirectly induce the differentiation of IL-10-producing regulatory B cells.




BACKGROUND:Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis o fmultiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy.
OBJECTIVES:The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titres and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients.
METHODS:Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml.
RESULTS:Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration.
CONCLUSIONS:RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.


Objective To investigate the relationship between the efficacy of interferon beta-1b (INF-β-1b) on relapsing-remitting multiple sclerosis (RRMS) and the Th17 cells in peripheral blood. 
Methods Eleven RRMS patients were enrolled and treated with 250 μg INF-β-1b for 6 months. Expanded disability status scale (EDSS) scrore and T2 lesion number on MRI were examined both at baseline and at the end of the study. Flow cytometry was used to detect the number of Th17 cells in peripheral blood before the treatment. 
Results Acoording to the EDSS scores, the 11 cases of RRMS were divided into two groups: the effective group and the ineffective group.The EDSS scores and the number of lesions on T2-weighted MRI were not different significantly between the two groups (P>0.05) before the treatment. But after the treatment, compared with the ineffective group, the EDSS scores and the number of lesions on T2-weighted MRI decreased significantly in the effective group (P<0.05). Compared with the effective group, the number of Th17 cells in the ineffective group increased significantly (P<0.01) before treatment. 
Conclusion Th17-mediated RRMS is nonresponsive to IFN-β-1b treatment.

Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S. IFN-beta inhibits human Th17 cell differentiation. J Immunol. 2009  15; 183: 5418-27


Immunology is not just black and white, it all depends on context

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